- Cardiovascular & Metabolic Diseases Graduate Program Track (CVMD)
- CeDER - Center for Diabetes and Endocrine Research
Health Science Campus
Block Health Science Building
2nd Floor, Room # 282
Director of Research Resources
Telephone: (419) 383-4182, 383-5307
FAX: (419) 383-2871
- A.A., Chemistry, 1966, Grand View College, Des Moines, Iowa
- B.A., Chemistry, 1969, Drake University, Des Moines, Iowa
- Ph.D., Biochemistry, 1976, Iowa State University, Ames, Iowa
- Post-doctoral Research Associate, Department of Biochemistry, University of Miami, 1976-1978
- Assistant Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1978-1984
- Associate Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1984-1992
- Professor of Physiology, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 1992-present
Regulated intracellular proteolysis and cell membrane repair.
It is now well appreciated that regulated proteolytic cleavage of key regulatory and structural proteins in cells is a major process governing many cell functions. My laboratory has been interested in how the calpains, calcium-requiring intracellular proteinases, contribute to membrane remodeling that must occur after mechanical damage to the plasma membrane surrounding cells. Cells in skeletal muscle, lung, intestine, skin and other tissues that are subject to constant mechanical insult have evolved a discrete mechanism to repair plasma membrane breaks that occur on an ongoing basis. The potential clinical importance of cell membrane repair is highlighted by recent studies on limb girdle muscular dystrophy-2B, which is caused by mutations in the protein dysferlin. Unlike Duchenne and Becker muscular dystrophies, LGMD-2B patients do not appear to have a weakened muscle cell membrane (sarcolemma). Recent studies from several different laboratories indicate that dysferlin functions in sarcolemma repair, and it is likely that the pathology associated with this dystrophy is related to failure to repair membrane rather than intrinsic membrane instability. Recent studies from my laboratory, in collaboration with Dr. Paul McNeil’s group at Medical College of Georgia, have indicated that calpains remodel localized cytoskeletal structures at the ruptured membrane in response to the flood of high extracellular calcium ion that enters the break. This “clearing” of localized cortical cytoskeleton is thought to allow the membrane fluidity necessary for spontaneous resealing, which is energetically favored once cytoskeletal protein attachments have been removed. My laboratory is currently investigating extracellular factors, including the serum protein fetuin-A, that may facilitate calpain-mediated membrane repair, and may be developed into clinically useful therapeutic agents for treatment of conditions associated with increased plasma membrane damage. We are also interested in whether calpains have more than a passive effect in repair: do they also facilitate active signal transduction pathways that trigger specific events, like localized actomyosin contraction, that may actively participate in membrane wound closure? Apart from defining roles for calpain, we are generally interested in exploring the plasma membrane “repairome” – the body of proteins, at present ill-defined, that participate in repairing mechanical damage to the plasma membrane.
- Mellgren, R.L. (1980) Canine cardiac calcium-dependent proteases: resolution of two forms with different requirements for calcium. FEBS Lett. 109:129-133.
- Mellgren, R.L. (1987) The calcium-dependent proteases: An enzyme system active at cellular membranes? FASEB J. 1:110-115.
- Mellgren, R.L., Lane, R.D. and Mericle, M.T. (1989) The binding of large calpastatin to biologic membranes is mediated in part by interaction of an amino terminal region with acidic phospholipids. Biochim. Biophys. Acta 999: 71-77.
- Mellgren, R.L. (1991) Proteolysis of nuclear proteins by µ-calpain and m-calpain. J. Biol. Chem. 266:13920-13924.
- Lane, R.D., Allan, D.M., and Mellgren, R.L. (1992) A comparison of the intracellular distribution of µ-calpain, m-calpain, and calpastatin in proliferating human A431 cells. Experimental Cell Research 203:5-16.
- Mellgren, R.L., Song, K., and Mericle, M.T. (1993) m-calpain requires DNA for activity on nuclear proteins at low calcium concentrations. J. Biol. Chem. 268:653-657.
- Mellgren, R.L. and Lu, Q. (1994) Selective nuclear transport of µ- calpain. Biochem. Biophys. Res. Commun. 204:544-550.
- Mellgren, R.L., Shaw, E., and Mericle, M.T. (1994) Inhibition of growth of human TE2 and C-33A cells by the cell-permeant calpain inhibitor benzyloxycarbonyl-leu-leu-tyr diazomethyl ketone. Exp. Cell. Res. 215:164- 171.
- Mellgren, R.L, Lu, Q., Zhang, W., Lakkis, M., Shaw, E., and Mericle, M.T. (1996) Isolation of a Chinese hamster ovary cell clone possessing decreased µ-calpain content and a reduced proliferative growth rate. J. Biol. Chem. 271:15568-15574.
- Zhang, W., Lane, R.D., and Mellgren, R.L. (1996) The major calpain isozymes are long-lived proteins: Design of an antisense strategy for calpain depletion in cultured cells. J. Biol. Chem. 271:18825-18830.
- Lu, Q. and Mellgren, R.L. (1996) Calpain inhibitors and serine protease inhibitors can produce apoptosis in HL-60 cells. Arch. Biochem. Biophys. 334:175-181.
- Zhang, W. and Mellgren, R.L. (1996) Calpain subunits remain associated during catalysis. Biochem. Biophys. Res. Commun. 227:890-896.
- Zhang, W., Lu, Q., Xie, Z-J., and Mellgren, R.L. (1997) Inhibition of the growth of WI-38 fibroblasts by benzyloxycarbonyl-Leu-Leu-Tyr diazomethyl ketone: Evidence that cleavage of p53 by a calpain-like protease is necessary for G1 to S-phase transition. Oncogene 14:255-263.
- Mellgren, R.L. (1997) Evidence for participation of a calpain-like cysteine protease in cell cycle progression through late G1 phase. Biochem. Biophys. Res. Commun. 236:555-558.
- Kakkar, R., Raju, R.V.S., Mellgren, R.L., Radhi, J., and Sharma, R.K. (1997) Cardiac high molecular weight calmodulin binding protein contains calpastatin activity. Biochemistry 36:11550-11555.
- Mellgren, R.L. (1997) Specificities of cell permeant peptidyl inhibitors for the proteinase activities of µ-calpain and the 20 S proteasome. J. Biol. Chem. 272:29899-29903.
- Huttenlocher, A., Palecek, S.P., Lu, Q., Zhang, W., Mellgren, R.L., Lauffenburger, D.A., Ginsberg, M.H., and Horwitz, A.F. (1997) Regulation of cell migration by the calcium-dependent protease calpain. J. Biol. Chem. 272:32719-32722.
- Mellgren, R.L., Zhang, W., Lu, Q. and Lane, R.D. (1999) Involvement of Calpains in Cell Cycle G1 to S-Phase Progression. In: "Calpain: Pharmacology and Toxicology of a Calcium-Dependent Cellular Protease", (Wang, K.K.W., and Yuen, P.-W., Eds.), pp. 161-168, Taylor & Francis, New York.
- Mellgren, R.L. (2000) A Radioimmunologic Technique for Assessing Calpain Activation in Cells. In: "Calpain Methods and Protocols" (Elce, J.S., Ed.), pp. 161-169, Humana Press, New Jersey.
- Xu, Y. and Mellgren, R.L. (2002) Calpain inhibition decreases the growth rate of mammalian cell colonies. J. Biol. Chem. 277:21474-21479.
- Lu, T., Xu, Y., Mericle, M.T., and Mellgren, R.L. (2002) Participation of the conventional calpains in apoptosis. Biochem. Biophys. Acta 1590:16-26.
- Spencer, M.J., and Mellgren, R.L. (2002) Overexpression of a Calpastatin Transgene in mdx Muscle Reduces Dystrophic Pathology. Human Mol. Gen.11: 2645-2655.
- Huang, X., Czerwinski, E., and Mellgren, R.L. (2003) Purification and properties of the dicytostelium calpain-like protein, Cpl. Biochemistry 42:1789-1795.
- Mellgren, R.L., and Huang, X. Fetuin A stabilizes m-calpain and facilitates plasma membrane repair. J Biol Chem. 2007 Dec 7;282(49):35868-77. Epub 2007 Oct 17.
- Mellgren, R.L., Zhang, W., Miyake, K. and McNeil, P.L. Calpain is Required for the Rapid, Calcium-dependent Repair of Wounded Plasma Membrane. J. Biol. Chem. 282:2567-2575, 2007. This article has been been highlighted as one of seven articles "of special or outstanding interest" in a recent review on plasma membrane repair in Current Opinion in Cell Biology 19:1-8, 2007.
- Mellgren, R.L. Detergent-resistant membrane subfractions containing proteins of plasma membrane, mitochondrial, and internal membrane origins. J Biochem Biophys Methods. 2008 Apr 24;70(6):1029-1036.